1. Field of the Invention
The present invention relates generally to the field of delivery of fluids and/or drugs to tissue, particularly to the electroosmotic delivery of fluid and/or drugs or other solutes to brain tissue.
2. Description of the Background
Drugs (e.g., biologically active small molecules, antibodies, nanoparticles) are administered to humans to treat a diversity of pathophysiological or disease states. Specific formulations for intravenous, oral, or other routes of administration are employed to deliver those drugs or solutes to patients or in research settings with animals or other biological systems. However, due to a variety of factors, including a limited ability of some drugs to pass across blood vessel walls (e.g., the blood-brain-barrier), direct administration of the drug to the target tissue itself is required.
Direct administration of a biologically active agent is traditionally accomplished by injection of a bolus of the drug or solute into the tissue of interest. Such convective flow procedures are accompanied by numerous complications. For example, the injection of fluid may cause damage to the tissue through physical deformation, both at the site of injection and along the path traversed by the cannula, resulting in the death or abnormal functioning of healthy tissue. Moreover, direct injection may not be effective due to a lack of penetration of the drug into certain dense target tissues (e.g., tumors) due to hypercellularity, altered tissue architecture, etc. Additionally, bulk injections of drug-containing fluid often results in backflow of fluid into and around the injection cannula, further reducing its potential efficacy and distribution.
Brain tumors represent a particularly appropriate target for direct drug administration. Malignant gliomas account for approximately 70% of new malignant primary brain tumor diagnoses each year in the United States. Moreover, gliomas are associated with disproportionately high morbidity and mortality, with only a 12 to 15 month median survival for patients with glioblastomas and 2 to 5 years for patients with anaplastic gliomas, irrespective of treatment. Gliomas represent a category of malignant primary brain tumors that originate from the supporting cells—oligodendrocytes and astrocytes—of the central nervous system. Recurrence of gliomas at the same or adjacent anatomical sites is routine observed. Such a pathological condition would indicate a benefit to a sustained and direct administration of chemotherapeutic agents.
Brain tissue also presents particular problems for convective, bolus injections of drug-containing fluids. Pressure-driven convection-enhanced delivery of solutions in clinical trials elucidated several complications related to controlling the direction of fluid flow. In these trials, infusions followed paths of least pressure resistance (which did not usually coincide with their target path), and often penetrated ependymal linings with uncontrolled ejections into the ventricular system, flowed backwards along the infusion cannula, or deformed brain tissue itself.
In contrast, electrokinetic transport of compounds provides a more controlled and reproducible mechanism for delivery of drugs to biological tissue. Electrokinetic transport in human or animal tissue represents the movement of molecules due to an applied electric field including electroosmosis and electrophoresis. Electroosmosis is the bulk fluid flow developed in a porous matrix with a non-zero zeta-potential, such as brain or other human or animal tissue, upon application of an electric field, while electrophoresis is the movement of a charged molecule itself in the electric field. Electrokinetic transport avoids many of the complications encountered in the traditional bulk injection of drugs into tissue in that it does not involve the pressure injection of large volumes of fluid into tissue. Furthermore, unlike pressure-induced convection-enhanced delivery, neither the porosity of the tissue being penetrated or the characteristic dimensions of the extracellular space are dominant factors in penetration depth of the drug. Transport is instead predominantly guided by the chemical properties of the drug and tissue rather than by the physical structure of the porous medium.
The present invention addresses the deficiencies of the prior art by providing a novel mechanism by which drugs may be administered to a patient in need thereof. The present invention takes advantage of the chemical properties of drugs, solutes, and target tissue to provide a mechanism for delivering a carefully controlled amount of drug to a target tissue, while minimizing problems associated with traditional bolus administration. The delivery methods and apparatuses of the present invention may be employed in a wide variety of physiological, research, and medical situations.